Indoline-3-carboxylic acid derived organocatalysts for the anti-mannich reaction

Article abstract of DOI:10.1002/chem.201002130

Mannich type reactions of a preformed aldimine with various carbonyl compounds were investigated with a series of functionalised indoline derivatives as catalysts: indoline-3-carboxylic acid, the diphenylcarbinol analogue and O-protected silyl ether analo

Full text of DOI:10.1002/chem.201002130

DOI: 10.1002/chem.201002130
Indoline-3-Carboxylic Acid Derived Organocatalysts for the anti-Mannich
Reaction
Jçrg Pietruszka* and Robert Christian Simon[a]
Abstract: Mannich type reactions of a
preformed aldimine with various car-
bonyl compounds were investigated
with a series of functionalised indoline
derivatives as catalysts: indoline-3-car-
boxylic acid, the diphenylcarbinol ana-
logue and O-protected silyl ether ana-
logues. All compounds were readily
prepared in enantiopure form by using
an enzymatic kinetic resolution as a
key step (E@100). The alcohol and
ether catalysts failed to induce com-
plete chirality transfer but did afford
the Mannich bases in good yields and
high diastereomeric ratios, whereas the
acid catalyst gave the products in a
highly diastereo- and enantioselective
manner. The absolute configuration of
the products was determined by a syn–
anti isomerisation protocol, initiated by
the sterically demanding base 1,8-
Keywords: Candida antarctica li-
pase B (CAL-B) · diastereoselectiv-
ity · epimerization · kinetic resolu-
tion · organocatalysis
diazabicycloACTHNUTRGNEU[GN 5.4.0]undec-7-ene.
Introduction
(DMSO, DMF, alcohols), high catalyst loadings (up to
20 mol%) are often essential and are accompanied by long
reaction times. Nevertheless, the concept of this reaction
type has been assumed and a whole series of catalysts with
various properties have been designed, most of them deriva-
tives of 1 (Scheme 1).[3c–l] The subject of this publication is
In the past decade, asymmetric organocatalysis has emerged
as a powerful tool for the synthesis of chiral building
blocks.[1] Nowadays, it represents an attractive alternative to
metal-based catalysts due to ease of handling, the availabili-
ty of both catalyst enantiomers, price and miscellaneous en-
vironmental aspects (for example, toxicity). The most inves-
tigated and predominant catalyst in this area is the naturally
occurring amino acid l-proline (1), which was found to be
very effective in the intramolecular aldol reaction (Hajos–
Parrish–Eder–Sauer–Wiechert reaction) in the early 1970s.[2]
Despite its simplicity, the amino acid 1 has been used since
then for a broad diversity of reactions, for example, inter-
and intramolecular aldol, Mannich type and Michael reac-
tions, aminations and cascade reactions, to furnish the prod-
ucts in good yield and often with good selectivity.[3a,b] Of
course, 1 is not a “universal asymmetric catalyst” and also
has its drawbacks. Beside the fact that most of the above
named reactions need to be conducted in polar solvents
Scheme 1. Organocatalysts successfully employed in the Mannich type re-
action.
the Mannich reaction,[4] which generates b-amino carbonyl
compounds or g-carbonyl-a-amino acid derivatives through
[a] Prof. J. Pietruszka, Dipl.-Ing. (FH) R. C. Simon
Institut fꢀr Bioorganische Chemie
der Heinrich Heine Universitꢁt Dꢀsseldorf
im Forschungszentrum Jꢀlich
Stetternicher Forst, Geb. 15.8, 52426 Jꢀlich (Germany)
Fax : (+49)2461-616196
ꢀ
C C bond formation. These structural motifs can be found
in a broad range of pharmaceuticals and are common in nat-
ural products, justifying the importance of this reaction.
Enantioselective approaches have not only been successfully
investigated with metal species,[5] but also utilising organoca-
talysts.[6] Proline (1), for example, has been proven to be a
E-mail: j.pietruszka@fz-juelich.de
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201002130.
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FULL PAPER
very efficient catalyst in the reaction with enolisable carbon-
yl compound donors. In all reported cases, the syn Mannich
bases were obtained in high diastereomeric ratio (d.r.) and
optical purity.[7] To overcome the lack of solubility, Ley and
co-workers designed a tetrazole derivative 2 (Scheme 1),
which was found to have a higher catalytic activity than 1
without loss of stereochemical control.[8] Other organocata-
lysts that have been successfully applied in the syn-selective
Mannich type addition are sulfonamidomethyl-pyrrolidine[9]
catalyst 8 should have similar free energies. Proton transfer
from the acid onto the aldimine 9 suggests that only the cis
ꢀ
conformer is properly positioned to allow C C bond forma-
tion. As a result, nucleophilic attack from the Si-face of the
enamine onto the Si-face of the aldimine 9 becomes possible
to furnish the anti isomers.[14]
The seminal work of the groups of List[15a,b] and See-
bach[15c,d] on proline catalysed reactions showed that there is
an additional equilibrium between the enamine and the oxa-
zolidine (derived from the addition of a carbonyl com-
pound) but the exact mechanism of the b-proline catalysis
remains unclear. Although some theoretical density func-
tional theory (DFT) studies were performed, in relation to
the position of the acidic function[16a] (a or b) and the ster-
eoselectivity,[16b] an oxazolidinone intermediate cannot be
ruled out.
3
(Tf=trifluoromethanesulfonyl) and 4-hydroxy-proline
(4).[7e]
The first asymmetric anti-selective organocatalyst, (S)-me-
thoxypyrrolidine (SMP, 5),[10] was reported in 2002 by
Barbas and Cꢃrdova who described isolation of the products
in high enantiomeric excess (ee) (up to 92%) and good
yield (up to 78%). From thereon, considerable efforts have
been devoted to find other catalysts that give the anti prod-
ucts in a highly diastereo- and enantioselective manner, but
the reports are still limited.[11] Nevertheless, further im-
provements could be achieved by changing the substitution
pattern in the pyrrolidine ring to produce highly anti-selec-
tive catalysts, such as the sulfonamide 6,[12] 5-methyl-b-pro-
line (7)[13] and b-proline (8)[14] (Scheme 1). Although 6 and 8
were very effective catalysts for the addition of preformed
N-p-methoxyphenyl (PMP) protected a-imino ethylglyoxa-
late (9) to aldehydes and ketones, catalyst 7 was ineffective
in the addition to ketones. The authors reasoned that the
low reactivity originated from the slow formation of the en-
amine intermediate 10 due to the disfavoured interaction
with the methyl group of the catalyst.[14a] The stereochemical
outcome of the reaction (with aldehyde donors) catalysed
by the b-proline catalysts 7 and 8 can be explained by a
boat-like transition state, in which a reversal of facial selec-
tivity is assumed (Scheme 2). In the case of catalyst 7, the
cis conformation of the enamine intermediate 10 ought to
be favoured because of the sterically demanding methyl
group at C-5; the enamine conformation 11 (s-cis/s-trans) of
As a part of our ongoing project to apply biocatalysts in
organic synthesis,[17] we report in detail our latest results on
the chemoenzymatic synthesis of indoline-3-carboxylic acid
(12) and derivatives 13–15 (TBS=tert-butyldimethylsilyl;
TMS=trimethylsilyl) and their application as organocata-
lysts in the anti Mannich reaction.[18]
Results and Discussion
We started our synthesis (Scheme 3) from methyl indole-3-
carboxylate (16), which was protected with Boc2O (Boc=
tert-butoxycarbonyl), under standard conditions, to furnish
17 in high yield (95%). Reduction of the double bond was
achieved with Mg in MeOH[19] (18, 93% yield), followed by
deprotection with trifluoroacetic acid (TFA) to give the rac-
emic ester 19 in very good yield (97%).
In a previous study of structurally related methyl-2,3-dihy-
dro-1H-indencarboxylate, conditions for an enzymatic kinet-
ic resolution were determined, established and optimised.[20]
Therefore, we could adapt those findings and added the
Scheme 2. Proposed transition state of b-proline catalysts 7 and 8 for the
indirect anti-selective Mannich type addition onto the preformed aldi-
mine 9.[12,13]
Scheme 3. Synthesis of rac-19. Reagents and conditions: a) NaH, Boc2O,
THF, 95%; b) Mg turnings, MeOH, 93%; c) TFA, CH2Cl2, 97%.
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14535

J. Pietruszka and R. C. Simon
enzyme CAL-B (Candida antarctica lipase B) to a stirred so-
lution of ester rac-19 in a potassium phosphate buffer
(pH 8.0; 100 mm). In contrast to our earlier results, we had
to decrease the temperature of the reaction mixture to 08C
because although the product (S)-12 was obtained in a re-
spectable 95% ee at room temperature, this was too low for
our purpose (full data not shown). At decreased tempera-
tures (08C), an ultimate enzymatic kinetic resolution was
obtained at 50% conversion with an enantioselectivity E@
100 (Scheme 4). Both products were obtained in nearly opti-
To further investigate the use of indoline derivates as
asymmetric organocatalysts, enantiopure ester (R)-19 was
subjected to a Grignard reaction to afford the diphenylcarbi-
nol (R)-13 in 51% yield (Scheme 6). a,a-Diaryl and silyl-
protected-a,a-diaryl catalysts have been exploited in differ-
ent reactions with remarkable success[23] therefore, the carbi-
nol (R)-13 was protected with a TBS or TMS group to
afford the silyl ethers (R)-14 and (R)-15, respectively.
Scheme 6. Synthesis of diphenylcarbinols 13–15. Reagents and condi-
tions: a) PhMgBr, Et2O, 51%; b) TBSTf, 2,6-lutidine, CH2Cl2, 83%;
c) TMSTf, 2,6-lutidine, CH2Cl2, 86%.
Determination of the absolute configuration: Prior to the in-
vestigation of the catalytic potential of compounds 12–15,
an analytical setup (HPLC) was needed for all transforma-
tions. Therefore, the syn products were synthesised accord-
ing to literature procedures in racemic and enantiopure
form (Scheme 7).[3c,7e]
Scheme 4. Enzyme-mediated synthesis of (R)- and (S)-acid 12.
cally pure form and in excellent yield [(R)-19: 49%, ee
>97%; (S)-12: 48%, ee >99%]. Furthermore, 2.50 g of rac-
19 were completely resolved within 4 h by using only 200 mg
of Novozyme435 (the immobilised form of Candida antarcti-
ca lipase B, Novo Nordisk, Denmark); the protein content
in Novozyme435 was determined to be 2%w/w of the total
mass.[21] A real catalytic ratio of 1:500 with respect to the
enzyme/substrate net weight was used. This enzymatic kinet-
ic resolution provides the first access to enantiopure (S)-12
and derivatives, which are promising precursors for the er-
goline framework, for example.[22a,b] The synthesis of acid
(R)-12 is also feasible. Whilst standard saponification leads
to racemisation of the ester 19, enzymatic hydrolysis of ester
(R)-19 with esterase BS3 (Codexis) furnishes the desired
acid (R)-12.
Scheme 7. Synthesis of syn Mannich bases catalysed by 1.
To determine the absolute configuration of the anti iso-
mers we used a method recently disclosed by our group; a
syn–anti epimerisation of aldehydes with 1,8-diazabicyclo-
The absolute configuration of the hydrolysed product (S)-
12 was determined by treating an analytical sample with
acetyl chloride (Scheme 5) to give the known acetamide (S)-
20 in 77% yield, under unoptimised conditions.[22c]
AHCTUNGTRENNUNG
[5.4.0]undec-7-ene (DBU) as base.[18] In contrast to previ-
ously described methods, which used imidazole as base for
the epimerisation of various carbonyl compounds,[24] a signif-
icant enhancement on the reaction rate was obtained
(20 min versus 17 h) by changing the base, without effect on
the outcome of the reaction. Although there is a major dif-
ference in the carbonyl activity of aldehydes and ketones,
our method ought to be transferable to ketones. As expect-
ed, the reaction times increased to 2.5 h for the ketones
(note: imidazole promoted epimerisation of a 3-pentanone
derived Mannich base took 7 days),[14a] HPLC (Figure 1)
1
and H NMR spectroscopic analysis revealed that no unde-
sired side reaction occurred. Thus, when the product syn-21
was epimerised at C-3 (B!A, Figure 1) all four possible iso-
Scheme 5. Determination of the absolute configuration by means of
chemical correlation.
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Indoline-3-Carboxylic Acid Organocatalysts
FULL PAPER
Table 1. Summary of the retention times of Mannich products 21–26,
based on the controlled epimerisation with DBU as base.
Compound
Retention times
HPLC conditions
AHCTUNGTRENNUNG
A
column: Chiralpak IA (Daicel)
flow rate: 0.5 mLminꢀ1
AHCTUNGTRENNUNG
AHCTUNGTREGUN(NN 2R,3R)-21=38.6 solv.: n-heptane/2-PrOH (92/8)
A
detection: l=220 nm
AHCTUNGTREGUN(NN 2R,3R)-22=13.1 column: Chiralpak IC (Daicel)
A
flow rate: 1.5 mLminꢀ1
solv.: n-hexane/2-PrOH (96/4)
detection: l=240 nm
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTREGUN(NN 2R,3R)-23=17.0 column: Chiralpak IC (Daicel)
A
flow rate: 1.5 mLminꢀ1
solv.: n-hexane/2-PrOH (98/2)
detection: l=250 nm
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTREGUN(NN 2R,3R)-24=28.4 column: Chiralpak IC (Daicel)
A
flow rate: 1.5 mLminꢀ1
solv.: n-hexane/2-PrOH (98/2)
detection: l=254 nm
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTREGUN(NN 2R,3R)-25=13.9 column: Chiralpak IC (Daicel)
A
flow rate: 1.5 mLminꢀ1
solv.: n-hexane/2-PrOH (96/4)
detection: l=240 nm
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTREGUN(NN 2R,3R)-26=13.5 column: Chiralpak IC (Daicel)
flow rate: 1.5 mLminꢀ1
solv.: n-hexane/2-PrOH (96/4)
detection: l=240 nm
Figure 1. Representative procedure for the determination of the absolute
configuration of the Mannich type reaction (controlled epimerisation of
racemic syn-21 and syn-(2S,3S)-21; DBU as base) and corresponding
HPLC traces (column: Chiralpak IA (Daicel) [length: 25 cm, average in-
ternal diameter: 0.46 cm], flow rate: 0.5 mLminꢀ1, eluent: n-heptane/2-
PrOH (92:8); Rt [(2R,3S)-21]=33.1 min, Rt [(2S,3S)-21]=35.8 min, Rt
[(2R,3R)-21]=38.6 min, Rt [(2S,3R)-21]=41.4 min). A: racemic mixture
of all diastereomers [rac-21] after epimerisation; B: syn diastereomers of
compound 21 prepared with rac-1; C: enantiopure (2S,3S)-21 prepared
with (S)-1; D: ~1:1 mixture of epimers (2S,3S)-21 and (2S,3R)-21, after
epimerisation.
G
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
Table 2. Indirect anti-selective Mannich reaction with diphenylcarbinol
rac-13 as catalyst.
mers were formed in almost equal amounts. Likewise, the
epimerisation of the enantiopure product (2S,3S)-21 afford-
ed the anti isomer (2S,3R)-21 in an almost equal amount
(C!D). This method was successfully applied for almost all
of the aldehyde- and ketone-derived Mannich bases as part
of our investigation (Table 1; not suitable for derivatives 27
and 28).
Entry
R
Product
Time
d.r.
[anti/syn]
Yield
[%]
AHCTUNGTRENNUNG
1[a]
2[a]
3[b]
4[b]
5[a]
6[a]
7[b]
iPr
tBu
Et
nBu
n-Hex
Me
Ph
(ꢁ)-anti-22
(ꢁ)-anti-23
(ꢁ)-anti-24
(ꢁ)-anti-25
(ꢁ)-anti-26
(ꢁ)-anti-27
(ꢁ)-anti-28
1 h
>98:2
>96:4
>98:2
>99:1
>97:3
>99:1
>98:2
79
74
78
95
90
93
–
12 h
0.5 h
0.5 h
3 h
10 min
1 h
Application: With a reliable analytical setup and the pure
compounds 12–15 in hand, we initially started to investigate
the catalytic efficacy of diphenylcarbinol 13. The reactions
were carried out with 15 mol% 13 at room temperature in
toluene (Table 2). In all cases, the reactions were highly dia-
stereoselective, which demonstrated the importance of the
b-functionality for anti stereocontrol. Moreover, excellent
yields of all products 22–28 were obtained (up to 95%) in a
short period of time. For instance, with propanal as the
donor, the Mannich product (ꢁ)-anti-27 could be obtained
in only 10 min and with a remarkable yield and selectivity
(93%, d.r.>99:1; Table 2, entry 6).
[a] RCHO (5 equiv). [b] RCHO (2 equiv).
Even very bulky substrates, such as isovaleraldehyde
(Table 2, entry 1) or 3,3-dimethylbutanal (Table 2, entry 2),
gave the respective products (ꢁ)-anti-22 and (ꢁ)-anti-23 in
high yield and diastereoselectivity, though the reaction times
were elongated. The best results were obtained by using n-
butanal as a donor (Table 2, entry 4). The product (ꢁ)-anti-
25 could be isolated in 95% yield with a d.r.>99:1 within
0.5 h. Thus, diphenylcarbinol rac-13 provides a superior
access to the anti isomers. During the construction of the an-
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J. Pietruszka and R. C. Simon
Table 4. Application of catalyst (R)-13 in the anti-selective Mannich type reaction.
alytical setup for compounds
21–28, we had to face two
major problems. Whilst com-
pound 27 was readily isolated
by filter flash chromatography
(the d.r. could be determined
by 1H NMR analysis of the
crude product), the product de-
Entry
Cat.
loading
R
Product
T
[8C]
Time
[days]
ee [%]
[anti]
d.r.
ACHTUNGTRENUN[NG anti/syn]
Yield
[%]
G
U
AHCTUNGTRENGN[UN mol%]
1[a]
2[a]
3[a]
4[b]
5[b]
20
20
20
15
15
iPr
iPr
nBu
nBu
nBu
(2S,3R)-22
(2S,3R)-22
(2S,3R)-25
(2S,3R)-25
(2S,3R)-25
ꢀ20
ꢀ45
ꢀ45
ꢀ20
ꢀ40
3
8
5
0.5
2.5
27
32
26
8
>98:2
>99:1
>99:1
94:6
>98:2
91
73
83
81
86
composes
HPLC conditions. In contrast,
compound 28 was not even
stable under chilled chromato-
graphic conditions (the instabil-
ity of the syn product was ob-
under
standard
E
E
N
U
34
[a] Toluene (5 mL per mmol 9). [b] Toluene (1 mL per mmol 9).
served previously by Janey and
co-workers[25] in their synthesis of the enzyme inhibitor
DPP-IV). Thus, no determination of the ee was possible at
this stage. To overcome this problem, both products were re-
duced with NaBH4 to the corresponding primary alcohols,
which underwent lactonisation during the workup proce-
dure. Based on the method previously described by Ley
et al.,[8] a modified procedure was developed for both com-
pounds with diphenylcarbinol rac-13 as a catalyst (Table 3).
To shorten the purification steps, the reduction was per-
formed immediately after the consumption of aldimine 9,
without isolation of the crude product.
The promising results concerning the yield and diastereo-
selectivity (Tables 2–4) prompted an NMR study to deter-
mine which step was responsible for the low enantioinduc-
tion reported in Table 4. Therefore, catalyst (R)-13 was al-
lowed to react with isovaleraldehyde at room temperature
in C6D6 and the reaction was monitored over 24 h. A stable
enamine intermediate 31 was found (Scheme 8, see Experi-
mental Section for full characterisation) but no unexpected
side reaction (for example, aldol reaction of the donor alde-
hyde) or decomposition was detected.
Table 3. Highly selective one-pot two-step synthesis of functionalised
amino lactones.
Scheme 8. 1H NMR experiment to determine if the aldehyde is responsi-
ble for the decomposition of catalyst 13 during the reaction.
Entry
R
Product
Time
d.r. [anti/syn]
Yield [%]
1
2
Me
Ph
(ꢁ)-syn-29
(ꢁ)-syn-30
70 min
2 h
>99:1
95:5
79
57
Additional experiments performed revealed that the di-
phenylcarbinol catalyst 13 decomposes during the reaction.
For this reason, silyl-protected catalysts 14 and 15 were in-
vestigated (Table 5). Both 14 and 15 were proven to be
As can be seen from Table 3, this technique worked well
and afforded syn lactones 29 and 30 without notable loss of
diastereoselectivity. Moreover, the improved reaction se-
quence provides rapid access to highly functionalised syn-1-
amino-2-alkyl- and syn-1-amino-2-aryl-g-lactones in good
yield (up to 79% over two steps). Enantiopure diphenylcar-
binol (R)-13 was next investigated under the same condi-
tions (room temperature, toluene). Whilst the yields and
diastereoselectivities were reproducible in all cases, the
enantioinduction was poor at room temperature (data not
shown). Another series of experiments were performed at
decreased temperatures (Table 4) with unsatisfactory results;
various concentrations, catalyst loadings and temperatures
were investigated with only moderate success. Notably, the
yields (up to 91%) and diastereoselectivity (d.r. up to
>99:1) were very high, but the ee did not exceed ~30%
(Table 4, entries 1, 2 and 5).
Table 5. Application of silyl-protected carbinols (R)-14 and (R)-15 in the
anti-selective Mannich reaction.
Entry R1
R
Product
T [8C] Time ee [%] d.r.
Yield
[h]
G
ACHTUNGTREN[NUNG anti/syn] [%]
1[a]
2[b]
3[a]
4[b]
5[a]
6[b]
TBS iPr
TBS nBu
TBS nBu
TBS nBu
TMS iPr
TMS nBu
N
30
12
30
48
48
72
rac
2
30
32
12
27
97:3
35
19
27
40
33
35
71:29
79:21
86:14
89:11
96:4
0
[a] Toluene (5 mL per mmol 9). [b] Toluene (1 mL per mmol 9).
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Indoline-3-Carboxylic Acid Organocatalysts
FULL PAPER
stable during the reaction and purification process but the
product yields, d.r. and ee were only moderate. The low
yields are caused by double Mannich condensation,[26]
whereas the low d.r. and ee may arise from the sterically de-
manding silyl protecting groups. Moreover, antagonistic ef-
fects were also observed. Highly concentrated reactions mix-
tures afforded the product 25 after a short period of time
(12 h, Table 5, entry 2), however, the side products prevailed
and the d.r. and ee were poor again. A slight improvement
was observed at higher dilution (ee=30%, d.r. [anti/syn]=
79:21, Table 5, entry 3). Interestingly, the activation barrier
for both product-forming steps was very low with catalyst
15. Upon performing the reaction at temperatures beneath
ꢀ108C almost no conversion could be detected after two
days, whilst at temperatures above ꢀ108C full conversion of
the aldimine 9 was observed. Thus, decreasing the tempera-
ture to further optimise the reaction was not feasible be-
cause of this barrier.
chemical outcome significantly depends on the temperature
applied; the decrease in temperature was accompanied by a
consistent improvement of diastereo- and enantioselectivity.
In the best case (ꢀ458C, 15 mol% catalyst loading) a d.r. of
98:2 with an ee of 90% was obtained (Table 6, entry 10).
Further experiments were performed to increase the reac-
tion rate by the addition of TFA (trifluoroacetic acid) but,
beside the fact that only racemic products were obtained
(Table 6, entry 9), the reaction time was considerably pro-
longed. A further decrease in temperature to ꢀ558C gave a
gratifying result; the product (2R,3S)-22 was formed in 55%
yield with a respectable 98:2 diastereoselectivity and ee>
98% (Table 7, entry 1). Moreover, we were surprised that
Table 7. Application of amino acid (S)-12 in the anti Mannich type reac-
tion.
Nevertheless, encouraged by these results we investigated
the aromatic amino acid (S)-12. Isovaleraldehyde was added
to preformed aldimine 9 under various conditions to afford
adduct (2R,3S)-22. A solvent screen with 10 mol% catalyst
loading gave disappointing results. Although high anti selec-
tivity was obtained in all solvents explored (Table 6, en-
Entry
Product
Time
[days]
ee [%]
[anti]
d.r.
ACHTUNGTRENUN[NG anti/syn]
Yield
[%]
G
G
1
2
3
4
5
6
7
5
>98
>98
>97
>97
>97
98/2
98/2
98/2
98/2
97/3
98/2
98/2
55
Table 6. Solvent effects in the indirect Mannich type reaction catalysed
by (S)-12.
10
5
70
73
Entry Solvent
Time
Cat.
T [8C] ee [%] d.r.
Yield
5
78
loading
A
AHCTUNGTRENGN[UN mol%]
1
2
3
4
5
6
7
8
9
DMSO
DMF
CH2Cl2
THF
MeCN
2-PrOH 2 days
15 h
18 h
20 h
30 h
10
10
10
10
10
10
5
RT
RT
RT
RT
14
11
25
22
23
7
68
72
rac
90
88:12
83:17
87:13
79:21
92:8
70:30
96:4
98:2
24
35
17
22
32
23
26
53
21
34
5
49
5
n. d.
<15[a]
1 days
+4
ꢀ20
ꢀ20
ꢀ40
ꢀ40
ꢀ45
toluene
toluene
21 h
3 days
2
>94
47[a]
10
10
toluene[a] 5 days
88:12
98:2
10
toluene
2.5 days 15
[a] Over two steps after reduction to the primary alcohol with NaBH4.
[a] 1 mol% Trifluoroacetic acid.
even at those low temperatures and inert conditions, double
Mannich condensation and transimination could not be fully
suppressed. As a compromise, we decided to investigate the
scope of the catalyst (S)-12 without further decreasing the
temperature, sustaining acceptable reaction conditions. Vari-
ous branched (Table 7, entries 1 and 2), linear (Table 7, en-
tries 3–6) and aromatic (Table 7, entry 7) aldehydes were
subjected to the established conditions. We were pleased to
find that most of the reactions performed gave almost exclu-
sively one single diastereomer (d.r. >97:3) in nearly perfect
enantioselectivity (ee up to >98%). Notably, even with 3,3-
dimethylbutanal, which does not react in the presence of
tries 1–7), low yields and almost no enantioinduction were
observed (Table 6, entries 1–6). During these attempts, we
found that the low yield results from the formation of sever-
al side reactions, for example, double Mannich condensa-
tion, decomposition of the aldimine 9 and transimination.
Clearly, the temperature had to be decreased to avoid side
reactions, as described earlier by other groups.[7f,12b] With
toluene as the best solvent with respect to the ee (68%) and
d.r. (96:4) (Table 6, entry 7), further optimisation studies
were performed by lowering the temperature from ꢀ20 to
ꢀ408C (Table 6, entry 7 versus 8). As expected, the stereo-
Chem. Eur. J. 2010, 16, 14534 – 14544
ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
14539

J. Pietruszka and R. C. Simon
proline (1) as catalyst,[7e] the Mannich adduct (2R,3S)-23
could be isolated in good yield (70%) and respectable d.r.
(>98:2) and ee (>98%) (Table 7, entry 2). Interestingly,
when phenylacetaldehyde was used as the donor, the reac-
tion time was only two days, despite the low temperature of
ꢀ558C. Furthermore, only a slight decrease in ee was ob-
served after the reduction with NaBH4. Thus, the product
(2R,3S)-28 was obtained in 47% yield and good stereoselec-
tivity (Table 7, entry 7). When propanal was used as the
donor almost no product could be obtained (Table 7,
entry 6). GC-MS analysis revealed that mostly the aldol
product of the donor aldehyde was formed. Various addition
methods of the aldehyde were investigated (dropwise; one
portion), but only <15% of the product could be isolated in
the best case.
Conclusion
A short and efficient reaction sequence was established for
the synthesis of enantiopure indoline-3-carboxylic acid ((S)-
12) that used an enzymatic kinetic resolution as the key step
(E @100).[27,28] The remaining ester, (R)-19, was subjected to
a Grignard reaction to afford a series of novel diphenylcar-
binols (R)-13–(R)-15 which were investigated in the anti
Mannich type reaction. Whilst acid (S)-12 afforded the
products in a highly diastereo- and enantioselective manner
(d.r. up to >98:2; ee up to >98%) under the optimised con-
ditions, the carbinol (R)-13 failed in the enantioinduction
due to decomposition. Even though, the anti Mannich bases
were obtained with amino alcohol (R)-13 in excellent yield
(up to 95%) and remarkable diastereoselectivity (d.r.
>99:1), the ee did not exceed ~30%. Furthermore, an im-
proved procedure for the determination of the absolute con-
figuration by controlled syn–anti isomerisation was estab-
lished for various aldehydes and ketones, by using DBU as
base.
We were also interested if catalyst (S)-12 allowed the con-
struction of Mannich bases when using ketones as donors.
Cyclohexanone was arbitrarily chosen and was reacted with
aldimine 9 in different solvents. In analogy to the aldehydes,
no enantio- and almost no diastereoselectivity was observed
at room temperature (Table 8). The best results concerning
Experimental Section
Table 8. Solvent screen of the reaction of (S)-12 with cyclohexanone.
All starting materials were obtained
from commercial suppliers and used as
received, unless stated otherwise. The
reactions were carried out with stan-
dard Schlenk techniques under Ar or
N2 atmosphere in oven-dried (1208C)
glassware. Solvents were dried and pu-
rified by conventional methods or by a
solvent purification system (MBraun)
prior to use. Preparative chromato-
graphic separations were performed
by column chromatography on Merck
silica gel 60 (0.063–0.200 mm). Solvents
for flash chromatography (petroleum
ether/ethyl acetate) were distilled
before use. Petroleum ether refers to a
fraction with a boiling point between
40–608C. TLC was carried out with
pre-coated plastic plates (Polygram
Entry
Solvent
Conditions
Time
ee [%]
[syn]
ee [%]
[anti]
d.r.
ACHTUNGTRENUN[NG syn/anti]
Yield
[%]
G
R
1[a]
2[a]
3[b]
4[a]
5[b]
6[a]
7[a]
8[a]
2-PrOH
toluene
toluene
MeCN
10 mol%, RT
10 mol%, RT
15 mol%, ꢀ208C
10 mol%, RT
20 mol%, ꢀ208C
10 mol%, RT
10 mol%, RT
10 mol%, RT
3 h
6 h
7 days
2 days
6 days
31 h
10
4
21
6
73
62
33
7
53:47
64:36
59:41
65:35
58:42
53:47
72:28
60:40
69
67
60
65
50
53
47
39
32
60
42
11
16
19
MeCN
DMSO
dioxane
2-Me-THF
23 h
20 h
10
25
[a] Solvent (5 mL per mmol 9). [b] Solvent (1 mL per mmol 9).
the solvent (MeCN and toluene) were further examined.
The temperature was decreased as was previously described
for the aldehydes (Table 6). The yields were moderate to
good in most of the reactions performed (up to 69%,
Table 8, entry 1) over a short period of time; at room tem-
perature all reactions were complete in <24 h, with excep-
tion of that conducted in DMSO (Table 8, entry 6). Interest-
ingly, a change of stereoselectivity compared with the alde-
hydes was observed. Whilst all the aldehydes gave almost
exclusively the anti isomers, cyclohexanone afforded the syn
adduct (d.r.=72:28 in the best case, Table 8, entry 7). We
reason that this might be caused by the steric interaction
with the aromatic ring. Nevertheless, a decrease of tempera-
ture to ꢀ208C (MeCN as solvent) improved the enantiose-
lectivity to 73% for the anti isomer (Table 8, entry 3) but
the major product was still the syn base. Thus, catalyst (S)-
12 is not suitable for the anti-selective Mannich type addi-
tion of ketones to the preformed aldimine 9.
SIL G/UV, Macherey–Nagel) with detection by UV (254 nm) and/or by
staining with cerium molybdenum solution [phosphomolybdic acid (25 g),
CeACHTUNTRGNEUNG(SO4)2·H2O (10 g), concd sulfuric acid (60 mL), H2O (940 mL)]. Opti-
cal rotation was measured at 208C on a Perkin–Elmer Polarimeter 241
MC against the sodium d-line. H and 13C NMR spectra were recorded at
1
208C on a Bruker Avance DRX 600 spectrometer; chemical shifts are
given in ppm relative to Me4Si (1H: Me4Si=0 ppm) or relative to the res-
onance of the solvent (13C: CDCl3 =77.0 ppm, MeOD=50.4 ppm).
See the Supporting Information for full details and all spectroscopic data.
1-tert-Butyl-3-methyl-1H-indole-3-carboxylate (17): According to the lit-
erature procedure,[29] 16 (1.87 g, 10.7 mmol) was dissolved in THF
(50 mL) and cooled to 08C, before NaH (333 mg, 13.9 mmol) was added.
After effervescence had ceased, Boc2O (3.03 g, 13.9 mmol) was added in
one portion, under vigorous stirring, whereupon
a precipitate was
formed. The mixture was allowed to warm to room temperature and
stirred overnight, then was extracted with CH2Cl2 (4ꢄ20 mL) against sa-
turated NH4Cl solution (100 mL). The combined organic layers were
dried over MgSO4, filtered and concentrated under reduced pressure.
The residue was purified by filter flash chromatography (petroleum
ether/ethyl acetate 95:5) and 17 was obtained in 95% yield (2.81 g,
14540
www.chemeurj.org
ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 14534 – 14544

Indoline-3-Carboxylic Acid Organocatalysts
FULL PAPER
10.21 mmol) as a colourless powder. Spectroscopic data are full in agree-
centrated under reduced pressure. Subsequent filter flash chromatogra-
phy (petroleum ether/ethyl acetate 80:20) afforded the ester (R)-19 in
49% yield (1.24 g, 7.00 mmol) as a yellow–brownish oil. Spectroscopic
data are as reported for the racemate (see above). [a]2D0 =ꢀ85.5 (c=0.81,
CHCl3, ee >97%).
ment with those reported in literature.[29] M.p. 127.08C (125–1278C)[29]
;
1H NMR (600 MHz, CDCl3): d=1.69 (s, 9H, C(Me)3), 3.94 (s, 3H,
OMe), 7.33–7.39 (m, 2H, arom.-H), 8.16 (m, 1H, arom.-H), 8.17 (brs,
1H, arom.-H), 8.27 ppm (s, 1H, 2-H); 13C NMR (151 MHz, CDCl3): d=
28.1 (C(Me)3), 51.5 (COOMe), 85.1 (C(Me)3), 112.2 (C-3), 115.2, 121.7,
124.0, 125.1 (arom.-CH), 127.5 (C-2), 132.0 (arom.-Cipso), 135.6 (arom.-
The remaining aqueous phase was concentrated under reduced pressure
at 308C on a rotary evaporator (elevated temperatures may lead to race-
misation). The residue was purified by filter flash chromatography (ethyl
acetate/methanol 90:10) to give acid (S)-12 in 48% yield (1.11 g,
6.80 mmol) as a colourless powder that turned brownish upon drying.
Obtained data are full in agreement with those reported in literature.[29]
C
ipso), 149.0 (NCO), 164.7 ppm (COOMe); IR (attenuated total reflec-
tance (ATR) film): n˜ =3170, 2977, 2948, 1811, 1743 (NC=O), 1707 (C=
O), 1557, 1451, 1367, 1244, 2241, 739 cmꢀ1; GC-MS (EI, 70 eV): m/z (%):
175 (39) [C10H8NO2+], 144 (100) [C9H6NO+], 116 (20) [C8H6N+]; elemen-
tal analysis calcd (%) for C15H17NO4 (275.30): C 65.44, H 6.22, N 5.09;
found: C 65.30, H 6.19, N 4.92.
[a]2D0 =+111.1 (c=1.06, MeOH, ee >99%); m.p. 177–1788C (180–
22c,28]
1818C);[
1H NMR (600 MHz, MeOD): d=3.54 (dd, J=9.6, 9.6 Hz,
1H, 2-Ha), 3.69 (dd, J=9.6, 7.8 Hz, 1H, 2-Hb), 4.04 (dd, J=9.6, 7.8 Hz,
1H, 3-H), 6.59 (d, J=7.8 Hz, 2H, arom.-H), 6.62 (dt, J=1.0, 7.5 Hz, 1H,
arom.-H), 6.94 (m, 1H, arom.-H), 7.18 ppm (ddt, J=0.6, 1.2, 7.5 Hz, 1H,
arom.-H); 13C NMR (151 MHz, MeOD): d=49.0 (C-3), 50.2 (C-2), 111.9,
120.6, 126.0 (arom.-CH), 128.8 (arom.-Cipso), 129.5 (arom.-CH), 152.5
(arom.-Cipso), 176.0 ppm (COOH); IR (ATR film): n˜ =3334 (NH), 2936,
2501, 1713 (C=O), 1463, 1376, 1241, 1200, 759 cmꢀ1; GC-MS (EI, 70 eV):
m/z (%)=163 (18) [M+], 117 (100) [C8H7N+]; elemental analysis calcd
(%) for C9H9NO2 (163.17): C 66.25, H 5.56, N 8.58; found: C 65.88, H
5.64, N 8.22.
1-tert-Butyl-3-methyl-1H-indoline-3-carboxylate (18): Mg turnings
(1.39 g, 57.1 mmol) were added in one portion to a stirred solution of 17
(3.14 g, 11.41 mmol) in MeOH (350 mL) and CH2Cl2 (100 mL) and gas
evolution was observed within 15 min (if necessary, the temperature of
the exothermic reaction was controlled with a water/ice bath). After all
the Mg had reacted (~2–3 h) and the starting material had completely
been converted (TLC control), the mixture was poured onto aqueous sa-
turated NH4Cl solution (500 mL) and was acidified to pH 4.0 with aque-
ous 2n HCl solution, whereupon the formed precipitate dissolved. The
aqueous layer was extracted with CH2Cl2 (4ꢄ25 mL) and EtOAc (1ꢄ
50 mL). The combined organic layers were dried over MgSO4, filtered
and concentrated under reduced pressure. Subsequent filter flash chro-
matography (petroleum ether/ethyl acetate 95:5) afforded 18 as colour-
less oil in 93% yield (2.95 g, 10.6 mmol). Spectroscopic data are full in
agreement with those reported in literature.[29] 1H NMR (600 MHz,
CDCl3): d=1.57 (s, 9H, C(Me)3), 3.78 (s, 3H, OMe), 4.10 (brs, 1H, 2-
Ha), 4.21 (dd, J=5.9 Hz, J=6.5 Hz, 1H, 3-H), 4.39 (brs, 1H, 2-Hb), 6.96
(dt, J=1.1, 7.5 Hz, 1H, arom.-H), 7.23 (t, J=7.7 Hz, 1H, arom.-H), 7.35
(d, J=7.6 Hz, 1H, arom.-H), 7.88 ppm (brs, 1H, arom.-H); 13C NMR
(151 MHz, CDCl3): d=28.5 (C(Me)3), 49.8 (C-2), 52.6 (COOMe), 81.0
(C(Me)3), 115.0, 122.3, 125.1 (arom.-CH), 129.0 (arom.-Cipso), 142.7
(arom.-Cipso), 152.1 (NCO), 171.9 ppm (COOMe); IR (ATR film): n˜ =
2977, 1739 (NC=O), 1698 (C=O), 1485, 1390, 1166, 1131, 1014 cmꢀ1; GC-
MS (EI, 70 eV): m/z (%): 176 (25) [C10H10NO2+], 118 (100) [C8H8N+]; el-
emental analysis calcd (%) for C15H19NO4 (277.32): C 64.97, H 6.91, N
5.05; found: C 64.75, H 7.04, N 4.76.
Enzymatic hydrolysis of ester (R)-19: A crude-cell-extract solution of es-
terase BS3 (Bacillus subitilis esterase 3, Codexis, 268 U/mL, stabilised in
glycerine, 400 mL) was added to
a stirred solution of ester (R)-19
(250 mg, 1.41 mmol, ee >97%) in potassium phosphate buffer (25 mL,
100 mm, pH 8.1) at 08C. The reaction was monitored with a pH electrode
and was kept at pH 8.1 by the addition of small portions of aqueous 1n
NaOH solution. After consumption of the theoretical amount of base,
the solution was concentrated under reduced pressure at 308C on a
rotary evaporator. Subsequent filter flash chromatography on silica
(ethyl acetate/MeOH 90:10) afforded acid (R)-12 in 68% yield (155 mg,
0.95 mmol) as a colourless powder, which turned brownish upon concen-
tration. Spectroscopic data are identical to those reported for the enan-
tiomer (see above). [a]2D0 =ꢀ106.3 (c=0.6, MeOH, ee>97%).
Determination of the ee of acid (S)-12 and ester (R)-19: The ee was de-
termined by chiral HPLC analysis (column: Chiralpak OD-H (4.6ꢄ
250 mm), solvent: n-hexane/2-PrOH=99.8:0.2, flow=0.75 mLminꢀ1, re-
tention time (Rt) [(3S)-32]=32.85 min, Rt [(3R)-32]=40.32 min) minutes
after derivatisation to methyl 1-(2,2,2-trifluoroacetyl)indoline-3-carboxyl-
ate (32) (Scheme 9).
Methyl indoline 3-carboxylate (rac-19): Trifluoroacetic acid (9.2 mL,
119.3 mmol) was added to a stirred solution of rac-18 (2.20 g, 7.95 mmol)
in dry CH2Cl2 (40 mL), under vigorous stirring at room temperature. The
reaction was stirred until no starting material could be detected by TLC
(1 h) and was then neutralised by the addition of small portions of aque-
ous saturated NaHCO3 solution at 08C. The mixture was extracted with
CH2Cl2 (4ꢄ10 mL) and the combined organic layers were dried over
MgSO4. After filtration and concentration under reduced pressure, the
residue was purified by filter flash chromatography (petroleum ether/
ethyl acetate 80:20) to give rac-19 in 97% yield (1.36 g, 7.67 mmol) as
yellow–brownish oil. Spectroscopic data are full in agreement with those
reported in literature.[29] 1H NMR (600 MHz, CDCl3): d=3.75 (dd, J=
9.6, 9.6 Hz, 1H, 2-Ha), 3.77 (s, 3H, COOMe), 3.94 (dd, J=9.6, 7.5 Hz,
1H, 2-Hb), 4.20 (dd, J=9.6, 7.5 Hz, 1H, 3-H), 6.67 (d, J=7.8 Hz, 1H,
arom.-H), 6.75 (dt, J=1.0, 7.5 Hz, 1H, arom.-H), 7.09 (m, 1H, arom.-H),
7.30 ppm (ddt, J=0.6, 1.2, 7.5 Hz, 1H, arom.-H); 13C NMR (151 MHz,
CDCl3): d=47.2 (C-3), 49.3 (C-2), 52.3 (COOMe), 110.1, 119.0, 125.2
(arom.-CH), 126.0 (arom.-Cipso), 128.8 (arom.-CH), 151.1 (arom.-Cipso),
172.7 ppm (CO); IR (ATR film): n˜ =3376 (NH), 2951, 2881, 1727 (C=O),
1604, 1488, 1464, 1434, 1316, 1251, 1196, 1170, 1019, 745 cmꢀ1; GC-MS
(EI, 70 eV): m/z (%): 177 (28) [M+], 118 (100) [C8H8N+].
Scheme 9. Derivatisation of acid (S)-12 and ester (R)-19.
Derivatisation of ester (R)-19: An analytical sample of (R)-19 (2 mL) was
treated with trifluoroacetic acid anhydride (10 mL) in an Eppendorf vial
and stirred vigorously at 308C on an Eppendorf Thermomix apparatus
for 10 min. Aqueous saturated NaHCO3 solution (500 mL) and n-heptane
(300 mL) were added. After effervescence had ceased and the layers had
separated, an aliquot of the organic layer (150 mL) was withdrawn and
analysed by chiral HPLC, as described above.
Enzymatic kinetic resolution of ester rac-19: In a typical run, (2.50 g,
14.11 mmol) of rac-19 was emulsified in potassium phosphate buffer
(150 mL, 100 mm, pH 8.0), under vigorous stirring at 08C. The enzyme
(200 mg, Novozyme435) was added and the pH was maintained at pH>
8.0 during the reaction by addition of aqueous 1n NaOH solution. After
the consumption of 95% of the theoretical amount, the enzyme was fil-
tered off and the aqueous phase was extracted with CH2Cl2 (5ꢄ20 mL).
The combined organic layers were dried over MgSO4, filtered and con-
Derivatisation of acid (S)-12: An analytical sample of (S)-12 (1 mg) was
treated with a solution of diazomethane in Et2O (1 mL, 0.45 m). After ef-
fervescence ceased, the solvent was removed on an Eppendorf Thermo-
mix apparatus (308C) and the residue was treated with trifluoroacetic
acid anhydride, as described above. M.p. 74.08C; 1H NMR (600 MHz,
Chem. Eur. J. 2010, 16, 14534 – 14544
ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
14541

J. Pietruszka and R. C. Simon
CDCl3): d=3.80 (s, 3H, COOMe), 4.35 (dd, J=4.8, 9.7 Hz, 1H, 2-Ha),
4.39 (dd, J=10.5, 9.7 Hz, 1H, 2-Hb), 4.75 (dd, J=4.8, 10.6 Hz, 1H, 3-H),
7.20 (dt, J=1.0, 7.6 Hz, 1H, arom.-H), 7.35 (m, 1H, arom.-H), 7.49 (d,
J=7.7 Hz, 1H, arom.-H), 8.22 ppm (d, J=8.1 Hz, 1H, arom.-H);
13C NMR (151 MHz, CDCl3): d=45.9 (C-2), 50.0 (C-3), 53.2 (COOMe),
118.4 (NCOCF3), 125.5, 126.3, 128.7 (arom.-CH), 129.7 (arom.-Cispo),
141.6 (NCOCF3), 171.0 ppm (CO2Me); 19F NMR (565 MHz, CDCl3): d=
72.6 ppm (s, 3F, CF3); IR (ATR film): n˜ =3071, 2970, 2942, 1734 (C=O),
1689 (C=O), 1485, 1440, 1253, 1190, 1136, 1082, 760 cmꢀ1; GC-MS (EI,
70 eV): m/z (%): 273 (42) [M+], 214 (100) [M+ꢀCO2Me], 117 (42)
[C8H7N+]; elemental analysis calcd (%) for C12H10F3NO3 (273.21): C
52.75, H 3.69, N 5.13; found: C 52.50, H 4.00, N 4.85.
duced pressure. Subsequent filter flash chromatography with a chilled
column (petroleum ether/ethyl acetate/triethylamine 95:4:1) afforded the
protected alcohol (R)-14 in 83% yield (513 mg, 1.23 mmol) as a colour-
less foam. [a]2D0 =ꢀ89.4 (c=1.28, CHCl3, ee >97%); m.p. 92–968C;
1H NMR (600 MHz, CDCl3): d=0.19 (s, 3H, SiMe), 0.20 (s, 3H, SiMe),
0.91 (s, 9H, C(Me)3), 2.26 (s, 1H, NH), 3.59 (dd, J=6.0, 10.5 Hz, 1H, 2-
Ha), 3.68 (dd, J=10.3, 10.4 Hz, 1H, 2-Hb), 4.63 (dd, J=6.0, 10.2 Hz, 1H,
3-H), 6.10 (d, J=7.5 Hz, 1H, arom.-H), 6.31 (td, J=1.0, 7.4 Hz, 1H,
arom.-H), 6.61 (d, J=8.0 Hz, 1H, arom.-H), 6.95 (m, 1H, arom.-H),
7.17–7.24 (m, 2H, arom.-H), 7.23–7.34 (m, 4H, arom.-H), 7.52–7.62 ppm
(m, 4H, arom.-H); 13C NMR (151 MHz, CDCl3): d=ꢀ4.44 (Si-CH3),
ꢀ4.38 (Si-CH3), 21.0 (C
ACHTUTGNRENNGU(CH3)3), 27.0 (CACHUTGNTREN(NUGN CH3)3), 50.6 (C-3), 53.5 (C-2),
80.4 (C-O), 110.5, 116.5, 126.0, 126.27, 126.30, 126.8, 127.0 (arom.-CH),
128.0 (arom.-Cipso), 128.4, 128.7 (arom.-CH), 146.1, 146.7, 155.0 ppm
(arom.-Cipso); IR (ATR film): n˜ =3550 (NH), 3061, 2927, 1597, 1480,
1249, 953, 743, 701 cmꢀ1; MS (ESI, 70 eV): m/z (%): 416 (100) [M+H+],
118 (17) [C8H8N+]; elemental analysis calcd (%) for C27H33NOSi
(415.64): C 78.02, H 8.00, N 3.37; found: C 78.00, H 7.94, N 3.20.
1-Acetyl-2,3-dihydroindoline-3-carboxylate [(S)-20]: NEt3 (127 mL,
919 mmol) was added to a stirred solution of (S)-12 (50.0 mg, 306 mmol)
in dry CH2Cl2 (5 mL) at 08C. After 5 min, AcCl (24.1 mL, 321 mmol) was
added dropwise. The mixture was allowed to reach room temperature
and stirred overnight. The solvent was removed with a rotary evaporator
and the residue was purified by filter flash chromatography (petroleum
ether/ethyl acetate/acetic acid 50:49:1) to afford the acetylated amino
acid (S)-20 as a colourless powder in 77% yield (48 mg, 234 mmol). Ob-
tained data are full in agreement with those reported in the literature.[21c]
[a]2D0 =+127.8 (c=0.18, MeOH, ee >99%); [a]2D0 =+129.1 (c=1.0,
MeOH, ee >99%);[21c] 1H NMR (600 MHz, [D6]DMSO): d=2.20 (s, 3H,
COMe), 4.26 (dd, J=14.1, 7.2 Hz, 1H, 2-Ha), 4.31 (dd, J=7.2, 8.8 Hz,
1H, 3-H), 4.33 (dd, J=14.1, 8.8 Hz, 1H, 2-Hb), 7.04 (dt, J=1.0, 7.5 Hz,
1H, arom.-H), 7.23 (dt, J=1.0, 7.5 Hz, 1H, arom.-H), 7.40 (d, J=7.5 Hz,
1H, arom.-H), 8.07 ppm (d, J=7.9 Hz, 1H, arom.-H); 13C NMR
(151 MHz, [D6]DMSO): d=24.0 (COCH3), 39.7 (C-3), 50.6 (C-2), 115.9,
123.2, 125.0, 128.3 (arom.-CH), 129.3, 142.5 (arom.-Cipso), 168.4 (COMe),
172.6 ppm (COOH); IR (ATR film): n˜ =2985, 1732 (C=O), 1668 (C=O),
1482, 1400, 746 cmꢀ1; GC-MS (EI, 70 eV): m/z (%): 160 (8) [M+ꢀCO2],
118 (100) [C8H8N+]; MS (ESI, positive ion): m/z (%): 206 (100) [M+].
Determination of the ee by HPLC: Column: Chiralpak IA (4.6ꢄ250 mm),
solvent: n-heptane/2-PrOH=98:2, flow=0.5 mLminꢀ1
,
detection l=
250 nm, Rt [(3S)-14]=10.89 min, Rt [(3R)-14]=14.85 min.
3-[Diphenyl(trimethylsilyloxy]methylindoline [(R)-15]:
2,6-Lutidine
(89 mg, 830 mmol) and TMSOTf (150 mg, 664 mmol) were added drop-
wise sequentially to stirred solution of alcohol (R)-13 (100 mg,
a
332 mmol) in dry CH2Cl2 (5 mL) at 08C. The reaction was allowed to
reach room temperature and stirred overnight, then quenched with half-
saturated aqueous NH4Cl solution (10 mL). The mixture was further di-
luted with EtOAc (50 mL) und washed with brine (2ꢄ50 mL). The or-
ganic phase was dried over MgSO4, filtered and concentrated under re-
duced pressure. Subsequent filter flash chromatography with a chilled
column (petroleum ether/triethylamine 98:2) afforded the protected alco-
hol (R)-15 in 86% yield (107 mg, 286 mmol) as a brownish oil. [a]D20
=
1
ꢀ37.3 (c=0.7, CHCl3, ee >97%); H NMR (600 MHz, CDCl3): d=ꢀ0.15
(s, 9H, SiMe3), 3.40 (s, 1H, NH), 3.57 (dd, J=5.7, 10.2 Hz, 1H, 2-Ha),
3.62 (dd, J=9.7, 10.1 Hz, 1H, 2-Hb), 4.61 (dd, J=5.7, 9.6 Hz, 1H, 3-H),
6.37 (dd, J=1.0, 8.2 Hz, 1H, arom.-H), 6.54 (dt, J=1.0, 7.5 Hz, 1H,
arom.-H), 6.92 (m, 2H, arom.-H), 7.24 (m, 8H, arom.-H), 7.36 ppm (m,
Indolin-3-yldiphenylmethanol (rac-13): The ester 19 (929 mg, 5.21 mmol)
was dissolved in dry Et2O (200 mL) at room temperature, before
PhMgBr (9.3 mL. 2.8m in Et2O) was added dropwise. The reaction was
allowed to stir overnight and PhMgBr (1 equiv) was added (TLC con-
trol). The reaction mixture was poured onto aqueous saturated NH4Cl
solution (100 mL) and washed with brine (2ꢄ20 mL). The organic layer
was dried over MgSO4, filtered and concentrated under reduced pressure.
Subsequent flash chromatography (petroleum ether/ethyl acetate 90:10)
afforded rac-13 in 51% yield (793 mg, 2.63 mmol) as a brownish powder.
M.p. 136–1388C; 1H NMR (600 MHz, CDCl3): d=3.51 (dd, J=6.9,
9.6 Hz, 1H, 2-Ha), 3.56 (dd, J=9.4 Hz, 1H, 2-Hb), 4.70 (dd, J=6.9,
9.2 Hz, 1H, 3-H), 6.14 (d, J=7.6 Hz, 1H, arom.-H), 6.45 (dt, J=1.1,
7.5 Hz, 1H, arom.-H), 6.63 (d, J=7.8 Hz, 1H, arom.-H), 7.02 (tq, J=0.6,
8.0 Hz, 1H, arom.-H), 7.19 (m, 1H, arom.-H), 7.24 (m, 1H, arom.-H),
7.29–7.35 (m, 4H, arom.-H), 7.56–7.60 ppm (m, 1H, arom.-H); 13C NMR
(151 MHz, CDCl3): d=49.8 (C-2), 50.8 (C-3), 79.8 ((Ph)2C-OH), 109.9,
118.4, 125.6, 126.0 (arom.-CH), 126.4 (arom.-Cipso), 126.6, 126.9, 128.3,
128.6 (arom.-CH), 146.1 (arom.-Cispo), 146.4 (arom.-Cispo), 153.3 ppm
(arom.-Cipso); IR (ATR film): n˜ =3326 (NH), 3200 (OH), 1600, 1488,
1447, 1247, 1165, 741, 701 cmꢀ1; GC-MS (EI, 70 eV): m/z (%): 301 (1)
[M+], 118 (100) [C8H8N+], 77 (88) [C6H5+]; elemental analysis calcd (%)
for C21H19NO (301.38): C 83.69, H 6.35, N 4.65; found: C 82.48, H 6.36,
N 4.48.
2H, arom.-H); 13C NMR (151 MHz, CDCl3): d=2.1 (Si
ACTHUNGTRNEUNG(CH3)3), 49.2 (C-
2), 51.9 (C-3), 84.0 (CO), 110.2, 118.2, 126.9, 127.2, 127.4, 127.5, 127.6,
128.1, 128.8, 128.9, 129.0 (arom.-CH), 144.0, 144.8, 153.5 ppm (arom.-
Cipso); IR (ATR film): n˜ =3389 (NH), 2953, 1607, 1249, 1066, 835,
700 cmꢀ1 GC-MS (EI, 70 eV): m/z (%): 373 (1) [M+], 255 (100)
;
[C16H19OSi+], 118 (27) [C8H8N+].
Determination of ee by HPLC: Column: Chiralpak IA (4.6ꢄ250 mm),
solvent: n-heptane/2-PrOH=96:4, flow=0.5 mLminꢀ1
250 nm, Rt [(3S)-15]=11.1 min, Rt [(3R)-15]=19.1 min.
, detection l=
General procedure for the addition of aldehydes to N-(p-methoxyben-
zyl)-a-imino ethyl glyoxalate (9) catalysed by (S)-12: Compound (S)-12
was added in one portion to a stirred solution of aldimine 9 (207 mg,
1.0 mmol) in dry toluene (5 mL). The mixture was stirred for 10 min,
cooled to ꢀ558C and treated with aldehyde (5 equiv). The reaction mix-
ture was stirred as indicated in Table 6 and was then purified by chilled
filter flash chromatography with varying mixtures of petroleum ether and
ethyl acetate.
General procedure for the addition of aldehydes to N-(p-methoxyben-
zyl)-a-imino ethyl glyoxalate (9) catalysed by (R)-13 or rac-13: Com-
pound (R)-13 or rac-13 (45 mg, 0.15 mmol) was added in one portion to a
stirred solution of aldimine 9 (207 mg, 1.0 mmol) in dry toluene (5 mL).
The mixture was stirred for 5 min and then treated with aldehyde
(2 equiv). The mixture was stirred as indicated in Table 1 and was then
subjected to chilled filter flash chromatography (no extraction necessary)
with varying mixtures of petroleum ether and ethyl acetate to afford the
corresponding anti Mannich base.
(R)-Indolin-3-yldiphenylmethanol [(R)-13]: The pure enantiomer was
prepared according to the procedure reported for the racemate above.
[a]2D0 =ꢀ93.4 (c=0.53, CHCl3, ee >97%). Determination of ee by HPLC:
column: Chiralpak IC (4.6ꢄ250 mm), solvent: n-hexane/2-PrOH=80:20,
flow=1.0 mLminꢀ1, Rt [(3R)-13]=7.0 min, Rt [(3S)-13])=8.44 min.
3-[(tert-Butyldimethylsilyloxy)diphenylmethyl]indoline [(R)-14]: 2,6-Lu-
tidine (400 mg, 3.73 mmol) and TBSOTf (987 mg, 3.73 mmol) were se-
quentially added to a stirred solution of alcohol 13 (450 mg, 1.49 mmol)
in dry CH2Cl2 (5 mL), dropwise at 08C. The reaction was allowed to
reach room temperature and stirred overnight, then quenched with half-
saturated aqueous NH4Cl solution (10 mL). The mixture was further di-
luted with EtOAc (50 mL) and washed with brine (2ꢄ50 mL). The or-
ganic layer was dried over MgSO4, filtered and concentrated under re-
Controlled epimerisation of the Mannich bases for the determination of
the absolute configuration: DBU (2 mL) was added to a stirred solution
of the Mannich base (1.0 mg) in dry CH2Cl2 (1.0 mL). The mixture was
vigorously stirred at room temperature. After 15 min (in the case of alde-
hydes) or 30 min (in the case of ketones), an aliquot (50 mL) was with-
14542
www.chemeurj.org
ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 14534 – 14544

Indoline-3-Carboxylic Acid Organocatalysts
FULL PAPER
drawn. The aliquot was extracted from saturated aqueous NH4Cl solution
(500 mL) with n-heptane (500 mL). An aliquot of the organic layer
(200 mL) was taken and analysed by chiral HPLC, as described above.
Evocatal for their kind donations and contributions to our research. Fur-
thermore, we thank the analytical departments at the University of Stutt-
gart and the FZ Jꢀlich, as well as Monika Gehsing, Rainer Goldbaum,
Verena Doum, Birgit Henßen, Erik Kranz, Christoph Lorenz, Vera Op-
hoven, Bea Paschold, Truc Pham, Saskia Schuback and Dennis Weidener
for their ongoing support.
(ꢁ)-syn-3-(4-Methoxyphenylamino)-4-methyldihydrofuran-2-one: Com-
pound rac-13 (45 mg, 0.15 mmol) and aldehyde (1.5 equiv) were added to
a stirred solution of aldimine 9 (207 mg, 1.00 mmol) in toluene (5 mL).
After full conversion had been detected (as judged by TLC, Table 3), the
reaction mixture was cooled to 08C, diluted with EtOH (5 mL) and treat-
ed with NaBH4 (378 mg, 10.0 mmol). The reaction was stirred at this tem-
perature for 1 h and then poured onto saturated aqueous NH4Cl solution
(100 mL). EtOAc (50 mL) was added and the organic phase was washed
with saturated aqueous NH4Cl (2ꢄ25 mL) and brine (1ꢄ50 mL). The
combined organic layers were dried over MgSO4, filtered and concentrat-
ed under reduced pressure. Subsequent filter flash chromatography (chil-
led column, petroleum ether/ethyl acetate 85:15) afforded the product in
79% yield (175 mg, 0.79 mmol) as an orange oil. 1H NMR (600 MHz,
CDCl3): d=1.0 (d, J=7.2 Hz, 3H, Me), 3.0 (dddq, J=5.0, 7.2, 7.2, 9.2 Hz,
1H, 4-H), 3.76 (s, 3H, OMe), 4.05 (brs, 1H, NH), 4.12 (dd, J=3.0,
7.1 Hz, 1H, 3-H), 4.14 (dd, J=9.2, 9.2 Hz, 1H, 5-Ha), 4.45 (dd, J=5.0,
9.2 Hz, 1H, 5-Hb), 6.62 (d, J=8.9 Hz, 2H, arom.-H), 6.81 ppm (d, J=
8.9 Hz, 2H, arom.-H); 13C NMR (151 MHz, CDCl3): d=12.6 (Me at C-
4), 35.2 (C-4), 55.8 (OMe at C-4’), 57.6 (C-3), 72.2 (C-5), 114.2, 115.0
(arom.-CH), 140.7, 152.9 ppm (arom.-Cipso), 176.1 (C-2); IR (ATR film):
n˜ =3378 (NH), 2968, 1769 (C=O), 1512, 1239, 1164, 820 cmꢀ1; GC-MS
(EI, 70 eV): m/z (%): 221 (100) [M+], 134 (54) [C8H8NO+].
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Determination of ee of the (S)-12 catalysed reaction by HPLC: Column:
Chiralpak IC (4.6ꢄ250 mm), solvent: n-hexane/2-PrOH=80:20, flow=
1.3 mLminꢀ1
, detection l=254 nm, Rt [(3R,4S)-29]=21.20 min, Rt
[(3S,4R)-29]=36.40 min.
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(ꢁ)-syn-3-(4-Methoxyphenylamino)-4-phenyldihydrofuran-2
ACHTUNGTRENN(UNG 3H)-one:
Compound rac-13 (45 mg, 0.15 mmol) and aldehyde (1.5 equiv) were
added to a stirred solution of aldimine 9 (207 mg, 1.00 mmol) in toluene
(5 mL). After full conversion had been detected (as judged by TLC,
Table 2), the reaction mixture was cooled to 08C, diluted with EtOH
(5 mL) and treated with NaBH4 (378 mg, 10.0 mmol). The reaction was
stirred at this temperature for 1 h and then poured onto of a saturated
aqueous NH4Cl solution (100 mL). EtOAc (50 mL) was added and the
organic phase washed with saturated aqueous NH4Cl (2ꢄ25 mL) and
brine (50 mL). The combined organic layers were dried over MgSO4, fil-
tered and concentrated under reduced pressure. Subsequent filter flash
chromatography (chilled column, petroleum ether/ethyl acetate 80:20) af-
forded the product in 60% yield (169 mg, 0. 60 mmol) as an orange
powder. M.p. 127–1308C; 1H NMR (600 MHz, CDCl3): d=3.53 (brd, J=
6.7 Hz, 1H, NH), 3.75 (s, 3H, OMe), 4.53 (ddd, J=0.9, 5.2, 8.0 Hz, 1H,
4-H), 4.52 (dd, J=6.7, 7.8 Hz, 1H, 3-H), 4.70 (dd, J=0.9, 9.8 Hz, 1H, 5-
Ha), 4.74 (dd, J=5.4, 9.8 Hz, 1H, 5-Hb), 6.54 (d, J=9.0 Hz, 2H, arom.-
H), 6.77 (d, J=9.0 Hz, 2H, arom.-H), 7.07 (m, 2H, arom.-H), 7.28 ppm
(m, 3H, arom.-H); 13C NMR (151 MHz, CDCl3): d=45.6 (C-4), 55.9
(OMe at C-4’), 58.4 (C-3), 71.3 (C-5), 127.9, 128.1, 129.2, (arom.-CH),
136.4, 140.3, 153.1 (arom.-Cipso), 175.7 ppm (C-2); IR (ATR film): n˜ =
3345 (NH), 1759 (C=O), 1409, 1133, 810 cmꢀ1; GC-MS (EI, 70 eV): m/z
(%): 283 (55) [M+], 134 (100) [C8H8NO+]; determination of ee of the (S)-
12 catalysed reaction by HPLC: column: Chiralpak IC (4.6ꢄ250 mm),
solvent: n-hexane/2-PrOH=80:20, flow=1.3 mLminꢀ1
, detection l=
254 nm, Rt [(3R,4S)-30]=22.66 min, Rt [(3S,4R)-30]=48.55 min.
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German federal state of North Rhine-Westphalia, the Jꢀrgen Manchot
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Chem. Eur. J. 2010, 16, 14534 – 14544
ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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Received: July 26, 2010
Published online: November 24, 2010
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